Use of boswellic acid for treating brain tumors

ABSTRACT

The present invention relates to the use of pure boswellic acid, a physiologically acceptable salt, a derivative, a salt of said derivative or a vegetable preparation containing boswellic acid for the preparation of a pharmaceutical composition for the treatment of brain tumours.

BACKGROUND OF THE INVENTION

The present invention relates to the use of pure boswellic acid, aphysiologically acceptable salt, a derivative, a salt of said derivativeor a vegetable preparation containing boswellic acid for the productionof a pharmaceutical composition for the treatment of brain tumours.

The present invention also relates to the use of pure boswellic acid, aphysiologically acceptable salt, a derivative, a salt of said derivativeor a vegetable preparation containing boswellic acid for the treatmentof brain tumours.

The possibilities known to date for the therapeutical treatment of braintumours are unsatisfactory:

So far, the possibilities for a treatment of malignant brain tumours areinsufficient. Neurosurgical removal of the brain tumours representssevere surgery and, depending on type, size and position of the braintumours, in many cases does not lead to the complete removal of themalignant tumours. For these reasons, the average survival of thepatients suffering from malignant brain tumours is only about 9 monthseven after a combined treatment including surgery and radiotherapy. Anadditional chemotherapy using the cytostatics known so far is able toachieve a prolongation of the survival of only about 10% (Lesser, G. J.,Grossman S., The chemotherapy of high-grade astrocytomas, Seminars inOncology, 1994, 21:220-235).

Glucocorticosteroids have been used for the symptomatic treatment which,however, are not able to effectively reduce the peritumoural brainoedemas so that their use does achieve the desired success.

SUMMARY OF THE INVENTION

Therefore, it is an object of the present invention to provide the useof preparations useful for the treatment of brain tumours, theinhibition of the peritumoural brain oedema as well as the growth oftumour cells, and for the destruction of the tumour cells. Inparticular, there is provided a preparation which, without exhibitingthe side effects and the reduced efficiency accompanying the use of thecytostatics employed to date for the therapy of tumours, allow asignificantly more efficient treatment of brain tumours. Thepharmaceutical composition or preparation, respectively, providedaccording to the invention is intended to show a lower toxicity and,therefore, to be well tolerated by the patients. Much research has beencarried out to provide a pharmaceutical composition of that type (DeVita, D., Helman, S., Rosenberg, S. A. (eds.), Cancer--Principles andPractice of Oncology, 4th edition, 1993, J. B. Lippincott Company,Philadelphia; Lesser, G. J., Grossman, S., The chemotherapy ofhigh-grade astrocytomas, Seminars in Oncology, 1994, 21:220-235),documenting the high demand for the creation of such a pharmaceuticalcomposition.

Now, it has been surprisingly found that boswellic acid, aphysiologically acceptable salt, a derivative, a salt of said derivativeor a vegetable preparation containing boswellic acid is effective forthe treatment of brain tumours.

DETAILED DESCRIPTION OF THE INVENTION

India's ayurvedic medicine uses pharmaceutical compositions containingpreparations from the plant Boswellia serrata for the treatment ofinflammation but also of rheumatism. However, there are no publicationscontaining evidence as to the treatment of brain tumours using thesepharmaceutical compositions. Due to the efficacy of preparations fromthe plant Boswellia serrata in the treatment of inflammable diseasesthis gum has already been examined with respect to its components. Thus,Pardhy & Bhattacharyya report (Ind. J. Chem., 16B:176-178, 1978) thatBoswellia serrata contains essentially the following components:

β-boswellic acid, acetyl-β-boswellic acid, acetyl-11-keto-β-boswellicacid, 11-keto-β-boswellic acid.

So far, no research is known concerning the efficacy of these compoundsfor the treatment of brain tumours.

In the following, the structural formulas of boswellic acid and some ofits derivatives are shown: ##STR1## R=H: 11-keto-β-boswellic acidR=acetyl: acetyl-11-keto-β-boswellic acid

R=formyl: formyl-11-keto-β-boswellic acid ##STR2## R=H: α-boswellic acidR=acetyl: acetyl-α-boswellic acid

R=formyl: formyl-α-boswellic acid

As boswellic acid, there is preferably used β-boswellic acid whichaccording to references has been isolated from Boswellia serrata orother known plants containing boswellic acid. The β-boswellic acid maycontain, in minor amount a- or g-boswellic acid. As physiologicallyacceptable salts of boswellic acid, there may be used the sodium,potassium, ammonium, calcium salts. As derivatives of boswellic acid,there may be used lower alkyl esters obtained by esterification of thecarboxyl group with an C₁ -C₆ alcohol, preferably the methyl ester, oresters obtained by esterification of the hydroxyl group with aphysiologically acceptable carboxylic acid. Preferred derivatives areβ-boswellic acetate, β-boswellic formate, β-boswellic acid methyl ester,acetyl-β-boswellic acid, acetyl-11-keto-β-boswellic acid, and11-keto-β-boswellic acid.

Further, according to the invention it is possible to use a vegetablepreparation containing boswellic acid. According to the invention, thereare used preparations obtained from the gum of Boswellia species(olibanum, incense).

Plants containing boswellic acid (syn.: boswellinic acid) are: Boswellia(serrata, papyrifera, frereana, carteri, thurifera, glabra,bhaw-dajiana, oblongata, socotrana and other members of this family).

An ethanolic extract from the gum of Boswellia serrata containing theabove mentioned boswellic acids proves to be especially efficient: theapplication of this preparation--in the following referred to asphytopharmacon H 15 (produced and sold by the company Ayurmedica,Pocking)--allows within a treatment period of seven days to achieve areduction of the peritumoural brain oedema of 22 to 48%. Ahistopathological examination of the tumour tissue of the patientstreated shows to be necrotic as far as possible, a fact that isextraordinarily exceptional. The vitality of the explanted cells isextraordinarily low and is about 3.5 to 4.5% in cell cultures. Usually,the vitality of such cells is about 80%. In contrast to the cells ofuntreated patients, the cells of the treated tumour tissue show notendency to proliferate within two weeks.

These experiments show that H 15 inhibits the peritumoural brain oedemaas well as tumour growth and leads to the death of the tumour cells.

Further, according to the invention there is the possibility that theuse is carried out together with other chemically pure pharmaceuticalagents and/or other vegetable drugs. Examples for such other chemicallypure pharmaceutical agents are the following:

Cytostatics, e.g. nimustine, carmustine, lomustine, methyl lomustine,semustine, methotrexate, teniposide, dacarbacine, procarbacine,temozolamide, topotecane, paclitaxel, streptococine, cisplatin, 5-fluorouracil; glucocorticosteroids, such as dexamethasone, prednisolone,methyl prednisolone, prednisone, hydrocortisol, cloprednole,betamethasone.

An example for such a vegetable drug is vincristine.

According to the invention, the boswellic acid is administered asrequired. Since it has a low toxicity, the dosage is not critical andcan be easily varied by the physician depending on the severity of thedisease, the weight of the patient to be treated and the duration of thetreatment.

For example, unit dosages may be administered once to four times perday. The exact dose depends on the route of administration and thecondition to be treated. Naturally, it can be required to carry outroutine variations of the dose depending on the age and weight of thepatient as well as the severity of the disease state.

The preparations used according to the invention can be formulated in amanner known per se using one or more of pharmaceutically acceptablecarriers or diluents. The preparations can be formulated for oral,parenteral, rectal, intracranial or intrathecal administration.Preparations of the compounds for oral administration are preferred.

The pharmaceutical preparations for oral administration may be in theform of tablets or capsules prepared according to procedures known perse together with pharmaceutically acceptable diluents, such as bindingagents (for example pregelatinated corn starch, polyvinylpyrrolidone orhydropropylmethyl cellulose), fillers (for example lactose, sucrose,mannitol, corn starch, microcristalline cellulose or calcium hydrogenphosphate); lubricants (for example stearic acid, polyethylenglycol,magnesium stearate, talc or silica); desintegration agents (for examplepotato starch, sodium starch glycolate or sodiumcarboxymethylcellulose); or wetting agents (for example sodium laurylsulfate). The tablets may be coated according to known procedures.Liquid preparations for oral administration can be for example in theform of aqueous or oily solutions, syrups, elixirs, emulsions orsuspensions, or can be in the form of a dry product for thereconstitution with water or another suitable carrier prior to use. Suchliquid preparations can be prepared according to procedures known per sewith pharmaceutically acceptable additives, such as suspension agents(for example sorbitic syrup, cellulose derivatives, glucose/sugar syrup,gelatin, aluminium stearate gel or hydrogenated edible fats);emulsifying agents (for example lecithin, arabic gum or sorbitanmonooleate); non-aqueous carriers (for example mandelic oil, oilyesters, ethyl alcohol or fractionated vegetable oils); and preservatives(for example methyl or propyl-p-hydroxy-benzoates or sorbic acid). Theliquid preparations can also contain buffers, flavouring agents,colouring agents, and sweetening agents known per se as required.

For parenteral administration the compounds may be formulated forinjection, preferably intravenous, intraarterial, intramuscular,intracranial, intrathecal or subcutaneous injections. Preparations forinjection can be in unit dosage form, e.g. in ampoules, or in multipledose containers with a preservative added. The preparations may be inthe form of suspensions, solutions, or emulsions in oily or aqueouscarriers, and may contain preparation additives such as suspending,stabilizing and/or dispersing agents, and/or agents for adjusting thetonicity of the solution. Alternatively, the active ingredient can be inpowder form for reconstitution with a suitable carrier, for examplesterile pyrogen-free water prior to use.

The compounds may also be formulated as rectal preparations such assuppositories, for example of the kind containing suppository basesknown per se, such as cocoa butter or other glycerides.

The following Examples illustrate the use according to the invention.

EXAMPLE 1

Tablets for oral administration

A. Direct compression

(1)

    ______________________________________    Active agent:    boswellic acid                                15-30   mg/tablet    (or pulverized drug, respectively,                                0.5-1.0 g/tablet)    Magnesium stearate BP       0.65    mg/tablet    Dry lactose                 80      mg/tablet    ______________________________________

The active agent is compounded together with the dry lactose, and themixture is screened. The obtained mixture is compressed to form tabletsusing a tablet-compressing machine.

(2)

    ______________________________________    Active agent:    boswellic acid                                15-30   mg/tablet    (or pulverized drug, respectively,                                0.5-1.0 g/tablet)    Magnesium stearate BP       0.7     mg/tablet    Microcristalline cellulose NF                                100     mg/tablet    ______________________________________

The active agent is screened and is compounded with the microcristallinecellulose and magnesium stearate. The obtained mixture is compressed toform tablets using a tablet-compressing machine.

B. Wet granulation

    ______________________________________    Active agent:    boswellic acid                                15-30   mg/tablet    (or pulverized drug, respectively,                                0.5-1.0 g/tablet)    Lactose BP                  150.0   mg/tablet    Starch BP                   30.0    mg/tablet    Pregelatinated corn starch BP                                15.0    mg/tablet    Magnesium stearate BP       1.5     mg/tablet    ______________________________________

The active agent is screened by a suitable sieve and is compounded withlactose, starch and the pregelatinated corn starch. Suitable volumina ofpure water are added, and the powder is granulated. After drying, thegranulate is sieved and mixed with the magnesium stearate. Then, thegranulate is compressed to form tablets by using a punch having asuitable diameter.

Tablets having a different composition can be produced by varying theratio of active agent to lactose or the weight of compression, and usinga suitable punch.

EXAMPLE 2

Capsules

    ______________________________________    Active agent: boswellic acid                              15-30   mg/capsule    (or granulated drug,      0.5-1.0 g/capsule)    respectively,    Free-flowing starch       150.00  mg/capsule    Magnesium stearate BP     1.00    mg/capsule    ______________________________________

The active agent is screened and mixed with the other components. Themixture is filled into hard gelatin capsules No. 2 using a suitableapparatus. Other capsules can be prepared by varying the filling weight,and, if required, varying the size of the capsule.

EXAMPLE 3

Syrup

    ______________________________________    Sucrose-free preparation  mg/5 ml dose    ______________________________________    Active agent:      boswellic acid                                  15-30    Hydroxy propyl methyl cellulose USP    (Viscosity type 4000)         22.5    Buffer    Flavouring agent    Colouring agent               as required    Preservative    Sweetening agent    Pure water         Q.s. to    5.0 ml    ______________________________________

The hydroxypropyl methyl cellulose is dispersed in pure water, cooledand afterwards mixed with an aqueous suspension containing the activeagent and the other components of the preparation. The solution obtainedis adjusted to its volume and mixed.

EXAMPLE 4

    ______________________________________    Suspension                mg/5 ml dose    ______________________________________    Active agent:     boswellic acid                                  15-30    (or pulverized drug, respectively,                                  0.5-1.0 g)    (or appropriate amount of dried drug    extract)    Aluminium monostearate        75.00    Sweetening agent    Flavouring agent              as required    Colouring agent    Fractionated coconut oil                      Q.s. to     5.00    ______________________________________

The aluminium monostearate is dispersed in approximately 90% offractionated coconut oil. The resulting suspension is heated to 115° C.under stirring, followed by cooling. The sweetening, flavouring andcolouring agents are added, and the active agent is dispersed. Thesuspension then is adjusted to volume with the remaining fractionatedcoconut oil and mixed.

EXAMPLE 5

Sublingual tablet

    ______________________________________    Active agent:   boswellic acid                               15-30   mg/tablet    (or drug extract, respectively,                               0.5-1.0 g/tablet)    Compressable sugar NF      50.5    mg/tablet    Magnesium stearate BP      0.5     mg/tablet    ______________________________________

The active agent is screened by passage through a suitable sieve,compounded with the other components and compressed using suitablepunches. Tablets of different strength can be prepared by varying theactive agent to carrier ratio or the compressing weight.

EXAMPLE 6

Suppositories for rectal administration

    ______________________________________    Active agent:  boswellic acid                                 15-30   mg    Witepsol H15.sup.+                   Q.s. to       1.0     g    ______________________________________     .sup.+ suitable quality of Adeps solidus Ph.Eur.

A suspension is made of the active agent in molten Witepsol and isfilled into suppository forms of 1 g using a suitable apparatus.

EXAMPLE 7

Injection for intravenous administration

    ______________________________________    Active agent:   boswellic acid                                15-30   mg/ml    Sodium chloride intravenous    infusion, BP, 0,9 wt. %/vol.                    Q.s. to     1       ml    Batch size      2500 ml    ______________________________________

The active agent is dissolved in a portion of the sodium chlorideintravenous infusion, the solution is adjusted to volume using sodiumchloride intravenous infusion, and the solution is thoroughly mixed. Thesolution is filled into clear 10 ml glass ampoules type 1 and is headspace sealed under nitrogen by melting off the glass. The ampoules aresterilized by heating in an autoclave at 120° C. for not less than 20minutes.

We claim:
 1. A method of treating a patient having a brain tumour and aperitumoral brain oedema, the method comprising adminstering to thepatient a pharmaceutical composition comprising a vegetable preparationcontaining boswellic acid, the component being present in an amounteffective to treat the brain tumour and treat the peritumoral brainoedema.
 2. The method of claim 1, wherein the pharmaceutical compositionis administered to inhibit peritumoural brain oedema and growth oftumour cells as well as for destroying tumour cells.
 3. The method ofclaim 1, wherein the vegetable preparation containing boswellic acid isan incense extract.
 4. The method of claim 1, wherein the pharmaceuticalcomposition is administered by a route selected from the groupconsisting of an oral, buccal, rectal, intramuscular, subcutaneous,intraarticular, intravenous, intracranial, and intrathecaladministration route.
 5. The method of claim 1, wherein thepharmaceutical composition is in a form selected from the groupconsisting of tablets, dragees, capsules, solutions, polymer-boundpreparations, and suppositories.